Cytolytic virus activation therapy for Epstein-Barr virus-driven tumors.

Maarten A Wildeman, Zlata Novalic, Sandra A W M Verkuijlen, Hedy Juwana, Alwin D R Huitema, I Bing Tan, Jaap M Middeldorp, Jan Paul de Boer, Astrid E Greijer

Departments of Head and Neck Oncology and Surgery and Medical Oncology, The Netherlands.

Clinical cancer research : an official journal of the American Association for Cancer Research 2012 Sep 15

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Nasopharyngeal carcinoma (NPC) is causally linked to Epstein-Barr virus (EBV) infection. Because all tumor cells carry EBV, the virus itself is a potential target for therapy. In these tumor cells, EBV hides in a latent state and expresses only a few non-immunogenic proteins for EBV maintenance and contributes to tumor growth. We developed a cytolytic virus activation (CLVA) therapy for NPC treatment, reactivating latent EBV, triggering immune recognition, and inducing susceptibility to antiviral therapy. CLVA therapy combines gemcitabine (GCb) and valproic acid (VPA) for virus activation and tumor clearance with (val)ganciclovir (GCV) as the antiviral drug to block virus replication and kill proliferating virus-infected cells. CLVA treatment was optimized and validated in NPC cell lines and subsequently tested in 3 Dutch patients with NPC that was refractory to conventional treatment. In NPC cell lines, both GCb and VPA can induce the lytic cycle of EBV. Their combination resulted in a strong synergistic effect. The addition of GCV resulted in higher cytotoxicity compared with chemotherapy alone, which was not observed in EBV-negative cells. CLVA therapy was analyzed in 3 patients with end-stage NPC. Patients developed increased levels of viral DNA in the circulation originating from apoptotic tumor cells, had disease stabilization, and experienced improved quality of life. Our results in the initial CLVA-treated patients indicate that the therapy had a biological effect and was well tolerated with only moderate transient toxicity. This new virus-specific therapy could open a generic approach for treatment of multiple EBV-associated malignancies. ©2012 AACR.

Citation

Maarten A Wildeman, Zlata Novalic, Sandra A W M Verkuijlen, Hedy Juwana, Alwin D R Huitema, I Bing Tan, Jaap M Middeldorp, Jan Paul de Boer, Astrid E Greijer. Cytolytic virus activation therapy for Epstein-Barr virus-driven tumors. Clinical cancer research : an official journal of the American Association for Cancer Research. 2012 Sep 15;18(18):5061-70